title: The GABA B receptor agonist CGP44532 and the positive modulator GS39783 reverse some behavioural changes related to positive syndromes of psychosis in mice.
abstract: OBJECTIVE
  An important role of GABAergic neurotransmission in schizophrenia was proposed a long time ago, but there is limited data to support this hypothesis. In the present study we decided to investigate GABA(B) receptor ligands in animal models predictive for the antipsychotic activity of drugs. The GABA(B) receptor antagonists CGP51176 and CGP36742, agonist CGP44532 and positive allosteric modulator GS39783 were studied.
  
  
  METHODS
  The effects of all ligands were investigated in MK-801- and amphetamine-induced hyperactivity tests. The anti-hallucinogenic-like effect of the compounds was screened in the model of head twitches induced by (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Furthermore, the effect of GS39783 and CGP44532 on DOI-induced frequency of spontaneous excitatory postsynaptic currents (EPSCs) in slices from mouse brain frontal cortices was investigated. The anti-cataleptic properties of the compounds were also assessed.
  
  
  RESULTS
  The GABA(B) receptor activators CGP44532 and GS39783 exhibited antipsychotic-like effects both in the MK-801- and amphetamine-induced hyperactivity tests, as well as in the head-twitch model in mice. Such effects were not observed for the GABA(B) receptor antagonists. DOI-induced increased frequency of spontaneous EPSCs was also decreased by the compounds. Moreover, CGP44532 and GS39783 inhibited haloperidol-induced catalepsy and EPSCs.
  
  
  CONCLUSIONS
  These data suggest that selective GABA(B) receptor activators may be useful in the treatment of psychosis.
authors.affiliation: Department of Neurobiology, Institute of Pharmacology PAS, 31-343 Kraków, Poland.
authors.forename: J M
authors.initials: JM
authors.lastname: Wierońska
authors.forename: M
authors.initials: M
authors.lastname: Kusek
authors.forename: K
authors.initials: K
authors.lastname: Tokarski
authors.forename: J
authors.initials: J
authors.lastname: Wabno
authors.forename: W
authors.initials: W
authors.lastname: Froestl
authors.forename: A
authors.initials: A
authors.lastname: Pilc
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced; D003517:Cyclopentanes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D058786:GABA-B Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology; D006948:Hyperkinesis / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010721:Phosphinic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011605:Psychoses, Substance-Induced / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018080:Receptors, GABA-B / Q000378:metabolism*; D013577:Syndrome; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: C112036:3-amino-2-(S)-hydroxypropyl-methyl-phosphinic acid; D003517:Cyclopentanes; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; D010721:Phosphinic Acids; D011743:Pyrimidines; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid